Secondary Inflammatory Reaction Research Articles

Meconium Peritonitis

In the second and third trimesters of pregnancy, hyperechogenic regions in the fetal abdomen can be used to identify meconium peritonitis (MP). According to studies on neonates, MP affects 1 in every 35,000 live births. The presence of an intrauterine ileal rupture causes a sterile chemical reaction that causes meconium peritonitis. The creation of fluid results in ascites, fibrosis, calcification, and cyst formation as a secondary inflammatory reaction. This process has four different outcomes, culminating in four types of meconium peritonitis: fibre adhesive, cystic, diffuse (diffuse), and healing. Below, we describe one case of fetal meconium peritonitis.

Autoeczematization Id reaction following candidal diaper dermatitis

Id reactions are secondary inflammatory reactions that develop from a remote, localized immunological insult. They may be caused by various fungal, bacterial, viral, and parasitic infections. Diaper dermatitis with psoriasiform Id eruptions is a rarely reported phenomenon. Herein, we report the case of an infant who developed candidal diaper dermatitis followed by generalized psoriasiform Id eruptions. Most authors report the resolution of diaper area lesions with topical antifungals with or without steroids and Id eruptions with topical steroids alone. Our patient showed complete resolution of all lesions with oral fluconazole alone.

Mimicking focal epileptic seizures‐episodic pain due to a facial foreign body in a puppy: Imaging characteristics and treatment

AbstractA 4‐month‐old female entire Cavalier King Charles Spaniel was referred for investigation into a 3‐week history of suspected focal onset seizures, characterised by head nodding and eyelid twitching. An inflammatory soft‐tissue reaction surrounding a suspected foreign body (FB) in the subcutaneous tissue and muscles at the level of the left maxilla in the caudal aspect of the left maxillary second molar was detected using MRI. The presence of the FB was confirmed ultrasonographically. This was found to be a grass seed upon surgical removal. The previously reported clinical signs resolved immediately after the surgery. It was suspected that the FB and secondary inflammatory reaction incited a form of trigeminal neuralgia manifesting as paroxysmal head nodding and facial twitching. A form of trigeminal neuralgia should be included in the differential diagnosis of facial focal motor seizures and should be investigated accordingly before initiating any antiepileptic treatment.

Methyl Gallate Improves Hyperuricemia Nephropathy Mice Through Inhibiting NLRP3 Pathway.

Hyperuricemia nephropathy (HN) is a form of chronic tubulointerstitial inflammation, caused by the deposition of monosodium urate crystals (MSU) in the distal collecting duct and medullary interstitium, associated with a secondary inflammatory reaction. Numerous published reports indicated that NLRP3 inflammasome pathway play crucial roles in HN symptoms. The present study aims to investigate the protective effects of methyl gallate on HN mice and the underlying mechanisms. An HN model was established by intraperitoneal injection of potassium oxide (PO) to assess the effect of methyl gallate on renal histopathological changes, renal function, cytokine levels and expressions of NLRP3-related protein in HN mice. Moreover, in vitro models of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs) were established to explore the mechanism of methyl gallate on NLRP3 inflammasome activation. The results showed that methyl gallate significantly ameliorated HN by inhibiting uric acid production and promoting uric acid excretion as well as ameliorating renal injury induced by NLRP3 activation. Mechanistically, methyl gallate is a direct NLRP3 inhibitor that inhibits NLRP3 inflammasome activation but has no effect on the activation of AIM2 or NLRC4 inflammasomes in macrophages. Furthermore, methyl gallate inhibited the assembly of NLRP3 inflammasomes by blocking the ROS over-generation and oligomerization of NLRP3. Methyl gallate was also active ex vivo against ATP-treated PBMCs and synovial fluid mononuclear cells from patients with gout. In conclusion, methyl gallate has a nephroprotective effect against PO-induced HN through blocking the oligomerization of NLRP3 and then exerting anti-inflammatory activity in the NLRP3-driven diseases.

Daidzein Alleviates Hypothalamic-Pituitary-Adrenal Axis Hyperactivity, Ameliorates Depression-Like Behavior, and Partly Rectifies Circulating Cytokine Imbalance in Two Rodent Models of Depression.

Depression is one very common mental health disorder which can cause morbidity and mortality if not addressed. Recent studies have provided strong evidence that depression may be accompanied by immune activation, secondary inflammatory reaction, and hyperactivity of the Hypothalamic Pituitary Adrenal (HPA) axis. It is well-known that it takes at least 2 weeks for conventional antidepressants, especially SSRIs (Selective serotonin reuptake inhibitors) to produce effects. To better understand the mechanism of antidepressant effects on depression and subsequently further elucidate the pathogenesis of depression, we selected phytestrogen daidzein (DD) to observe its effects on the depression-like and anxiety-like behavior in two different rodent models of depression which were induced by learned helplessness and chronic mild stress (CMS) and then simultaneous evaluation of the depression-like behavior, the activity of HPA axis, and circulatory cytokines. Our results showed that daidzein attenuated depression-like behaviors through alleviating HPA axis hyperactivity, decreasing the levels of stress-related hormones, and partly rectifying some inflammatory cytokines imbalance in both the rodent models of depression.

Role of Cytokines Released During Pyroptosis in Non-Small Cell Lung Cancer.

PurposePyroptosis is a recently discovered highly inflammatory form of programmed cell death, during which the N-terminus of the cleaved Gasdermin protein family forms pores in the cell membrane, leading to cell disintegration and the release of certain intracellular factors, including caspase3, gasdermin E (GSDME), and high mobility group proteins (HMGB1), which trigger a series of secondary inflammatory reactions. Specifically, caspase3 can lyse GSDME and induce pyrolysis, while HMGB1 is released passively after cell membrane destruction. In this study, the roles of these proteins in lung cancer tissues as well as their clinical significance were investigated.Patients and MethodsThe expression levels of GSDME, caspase3, and HMGB1 proteins in lung cancer and paracancerous tissues were determined via immunohistochemical staining, and their relationship with the clinical stage, pathological grade, and survival prognosis of the patients was analyzed. Further, CD8+ T cell accumulation in the above-mentioned tissues was also determined, and differences between them with respect to CD8+T cell distribution were also investigated. Furthermore, the relationships between CD8+ T cell abundance and the expression levels of the above-mentioned proteins were determined via statistical analyses.ResultsLung cancer and paracancerous tissues showed significantly different GSDME, caspase3, and HMGB1 protein expression levels. GSDME expression level and the presence or absence of lymph node invasion were identified as prognostic indicators of survival in patients with lung cancer. Surprisingly, however, HMGB1, which showed a certain level of correlation with the presence or absence of lymph node metastasis, could not be used as a prognostic indicator of survival.ConclusionGSDME may be an important prognostic indicator of survival in patients with lung cancer. However, the effects of HMGB1 expression level and CD8+ T cell abundance on the prognosis of patients with lung cancer still need further investigation.

MiRNA-146a and miRNA-202-3p Attenuate Inflammatory Response by Inhibiting TLR4, IRAK1, and TRAF6 Expressions in Rats following Spinal Cord Injury

Spinal cord injury (SCI) is a catastrophic disease that induces a complex cascade of cellular reactions at the local lesion area, including secondary cell death and inflammatory reactions. Accumulating evidence has showed pro- and anti-inflammatory roles of microRNAs (miRNAs), a class of small RNAs, in SCI. The present study is aimed at investigating the effects of two miRNAs, miRNA-146a and miRNA-202-3p, on inflammatory response after SCI. Initially, we found that the expression levels of miRNA-146a and miRNA-202-3p were increased in the plasma samples of 32 SCI patients at days 3 and 7 after admission and the rat spinal cord at days 3 and 7 after SCI modeling compared with healthy controls and sham-operated rats, respectively. The expression levels of TLR4, IRAK1, and TRAF6 were declined in the rat spinal cord at days 1, 3, and 7 after SCI modeling compared with sham-operated rats. Injection of miRNA-146a mimic or miRNA-202-3p mimic decreased TLR4, IRAK1, and TRAF6 expressions in the rat spinal cord at days 1, 3, and 7 after SCI modeling, while injection of miRNA-146a antagomir or miRNA-202-3p antagomir produced opposed results. Subsequent results showed that the expression levels of tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 were upregulated in the rat serum at days 1, 3, and 7 after SCI modeling compared with sham-operated rats. Injection of miRNA-146a mimic or miRNA-202-3p mimic decreased TNF-α, IL-1β, IL-6, and IL-8 expression levels in the rat serum at days 1, 3, and 7 after SCI modeling, while injection of miRNA-146a antagomir or miRNA-202-3p antagomir yielded opposed results. The expression levels of TNF-α, IL-1β, IL-6, and IL-8 were higher in the supernatants of PC12 cells transfected with anti-miRNA-146a or anti-miRNA-202-3p than in those transfected with si-TLR4, si-IRAK1, or si-TRAF6. These findings support the notion that miRNA-146a/miRNA-202-3p exerts anti-inflammatory functions after SCI.

IFN-γ regulates the transformation of microglia into dendritic-like cells via the ERK/c-myc signaling pathway during cerebral ischemia/reperfusion in mice

Cerebral ischemia-reperfusion injury induces a secondary immune inflammatory reaction that exacerbates brain injury and clinical prognosis. Dendritic cells (DCs) and microglia are both important regulators of neuroinflammation. Studies have confirmed that a large number of cells express the DC surface marker CD11c in the ischemic area, and some of these cells also express microglial markers. However, the specific mechanism of transformation between microglia and DCs and their roles in the process of cerebral ischemia-reperfusion injury are still not clear. In this study, we established a mouse model and flow cytometry was used to detect the expression of mature DC surface molecules in activated microglia. IFN-γ knockout mice were used to determine the regulatory effect of IFN-γ on microglial transformation. We found that CD11c+ cells were derived from microglia after ischemia-reperfusion injury, and this group of cells highly expressed MHC-II molecules and other costimulatory molecules, such as CD80 and CD86, which were regulated by IFN-γ and its downstream signaling molecules ERK/c-myc. In summary, our results showed in cerebral ischemia-reperfusion injury, IFN-γ regulates the transformation of microglia to DC-like cells. Microglial-derived DC-like cells possess the ability to present antigens and activate naïve T cells which is regulated by the ERK/c-myc signaling pathway.

Intravenously Infusing the Secretome of Adipose-Derived Mesenchymal Stem Cells Ameliorates Neuroinflammation and Neurological Functioning After Traumatic Brain Injury.

The secretome of mesenchymal stem cell (MSC) offers a series of immunoregulatory properties and is regarded as an effective method of mitigating secondary neuroinflammation induced by traumatic brain injury (TBI). The secretome of adipose-derived MSCs (ASC-ST) was collected under hypoxia conditions. Proteomics data were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and concentrations of major components were tested. After the TBI caused by an electric cortical contusion impactor, rats were injected ASC-ST through caudal veins for 7 days. The neurological functional prognosis of TBI rats was significantly improved, and the vasogenic edema of brain tissues that was measured 14 days after TBI was relieved by ASC-ST, corresponding to brain water content levels. ASC-ST ameliorated TBI-induced neuroinflammatory environments that caused the edema, the apoptosis of the neural cells, and the nerve fiber damage by increasing the number of M2 phenotypes present while reducing the number of M1 phenotype microglia present. Furthermore, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were reduced, whereas transforming growth factor-beta (TGF-β) and tumor necrosis factor-stimulated gene 6 protein (TSG-6) levels were increased after secretome treatment. Altogether, ASC-ST is capable of improving neural functioning by modulating TBI-induced neuroinflammation and its related secondary insults. ASC-ST may be one of the most promising candidates for regulating the secondary inflammatory reactions of central nervous systems for clinical use.

The Involvement and Therapy Target of Immune Cells After Ischemic Stroke.

After ischemic stroke, the integrity of the blood-brain barrier is compromised. Peripheral immune cells, including neutrophils, T cells, B cells, dendritic cells, and macrophages, infiltrate into the ischemic brain tissue and play an important role in regulating the progression of ischemic brain injury. In this review, we will discuss the role of different immune cells after stroke in the secondary inflammatory reaction and focus on the phenotypes and functions of macrophages in ischemic stroke, as well as briefly introduce the anti-ischemic stroke therapy targeting macrophages.

Systemic inflammatory response after hyperthermic intraperitoneal chemotherapy (HIPEC): The perfusion protocol matters!

BackgroundCRS/HIPEC gained acceptance as a treatment for selected patients with peritoneal metastasis. However, the pathophysiology behind HIPEC is poorly understood, and a variety of regimens are currently in use. In this study, we describe for the first-time changes in the postoperative systemic inflammatory reaction, highly different among HIPEC treatment protocols. MethodsHIPEC was performed with three protocols, different with regard to perfusion times and drugs: (mitomycinC/doxorubicin, 90min), (cisplatin, 90min) (oxaliplatin, 30min). Serial blood samples were assessed for C-reactive protein (CRP), white blood cells (WBC), pancreatic stone protein (PSP) and bacterial component (16s rDNA). The study was approved by the local ethics committee and registered at clinicaltirals.gov (NCT02741167). ResultsOverall, 140 patients from two European centers were included. In patients without postoperative complications, a secondary peak of inflammatory parameters, CRP (p = 0.015) and PSP (p = 0.004) was observed after HIPEC for 90 min with mitomycinC/doxorubicin or cisplatin but not after 30 min oxaliplatin. In patients after 90 min HIPEC, postoperative serum bacterial 16srDNA level were 2.1 times higher (95% CI 0.646–3.032, p = 0.015) compared to 30 min oxaliplatin. DiscussionIn conclusion, we identified a secondary inflammatory reaction after 90 min HIPEC, either with mitomycinC/doxorubicin or cisplatin, not observed after short course HIPEC with oxaliplatin. This protocol dependent physiology of acute phase proteins should be known in the clinical management of patients after HIPEC.

The Ethanolic Extract of Eysenhardtia polystachya (Ort.) Sarg. Bark and Its Fractions Delay the Progression of Rheumatoid Arthritis and Show Antinociceptive Activity in Murine Models.

Eysenhardtia polystachya is widely used in folk medicine as an anti-rheumatic and analgesic agent, but no systematic study of its effects on several markers associated with rheumatoid arthritis and its ethnomedical use as analgesic agent has been performed. We evaluated the anti-arthritic and antinociceptive properties of an ethanolic extract of E. polystachya (EE) bark and its rich-flavonoids fractions in murine models. The EE was administered orally at doses of 25, 50, 100, and 200 mg/kg/day, and its fractions at 25 mg/kg/day in all animal models. Anti-arthritic activity was evaluated using a complete Freund´s adjuvant (CFA)-induced rheumatoid arthritis model in rats. The severity of arthritis was evaluated by changes in paw oedema, body weight, arthritic index, radiological scores, histological assessment of synovial joints, erythrocyte sedimentation rate, haematocrit, haemoglobin, serum rheumatoid factor, serum C-reactive protein and serum levels of the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IL-18, IFN-γ, GM-CSF, and anti-inflammatory cytokines IL-4, IL-10, IL-13. Antinociceptive activity was evaluated using an acetic acid-induced abdominal contraction test and a hot-plate test in mice. EE and its rich-flavonoids fractions inhibited secondary inflammatory reactions, diminished the specific histopathological alterations in the joint capsule and reduced the serum concentrations of the pro-inflammatory cytokines IL-6, TNF-α, and GM-CSF in arthritic rats. EE also reduced the number of writhes produced by acetic acid and increased the response time on the hot plate for mice. Our findings support the use of Eysenhardtia polystachya bark for the treatment of rheumatoid arthritis and pain management.

Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens.

Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4+T/CD8+T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections.

Potential Avoidance of Adverse Analgesic Effects Using a Biologically “Smart” Hydrogel Capable of Controlled Bupivacaine Release

Acute pain remains a tremendous clinical and economic burden, as its prevalence and common narcotic-based treatments are associated with poorer outcomes and higher costs. Multimodal analgesia portends great therapeutic promise, but rarely allows opioid sparing, and new alternatives are necessary. Microparticles (MPs) composed of biodegradable polymers [e.g., poly(lactic-co-glycolic acid) or PLGA] have been applied for controlled drug release and acute pain treatment research. However, foreign particles' presence within inflamed tissue may affect the drug release or targeting, and/or cause a secondary inflammatory reaction. We examined how small alterations in the particulate nature of MPs affect both their uptake into and subsequent activation of macrophages. MPs composed of PLGA and chitosan (PLGA-Chi) loaded with bupivacaine (BP) were engineered at different sizes and their opsonization by J774 macrophages was assessed. Uptake of PLGA-Chi by macrophages was found to be size dependent, but they were not cytotoxic or proinflammatory in effect. Moreover, encapsulation of MPs in a thermoresponsive loading gel (pluronic F-127) effectively prevented opsonization. Finally, MPs displayed sustained, tunable release of BP up to 7 days. These results demonstrate our ability to develop a drug delivery system capable of controlled release of local anesthetics to treat acute/subacute pain while concurrently avoiding enhanced inflammation.

Melatonin improves functional outcome via inhibition of matrix metalloproteinases-9 after photothrombotic spinal cord injury in rats.

Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9 play an important role in secondary inflammatory reaction and blood-central nervous system (CNS) barrier disruption after spinal cord injury (SCI). Theoretically, it is expected that early blockade of activation of MMPs can provide neuro-protective effects from secondary tissue damage and improve functional neurological outcomes. The aim of this study was to investigate the expression and the activity of MMP-2 and MMP-9, and to determine the regulatory effect of melatonin on MMP expression and activity after photochemically induced SCI in rats. Female Sprague-Dawley rats weighing between 250 and 300 g (age 8 weeks) received focal ischemia by photothrombosis using Rose Bengal (RB). The injured animals were divided into two groups; one group received 50 mg/kg of melatonin intraperitoneally, starting 1 h after injury and at 12 h intervals for 7 days, while animals in the control group received weight-adjusted doses of a saline vehicle. In each group, the expressions and activities of MMP-2 and MMP-9 were assessed by Western blot and gelatin zymography at various times from 6 h to 3 days. The locomotor function was assessed using the Basso-Beattie-Bresnahan (BBB) scale at 3 days after SCI and then once per week for 4 weeks. The animals were killed at 28 days after the injury, and the histopathology of the lesions was assessed. The expressions and activities of MMP-9 were increased at 6, 24, 48, and 72 h after SCI in the control group. In the melatonin-treated group, the expression of MMP-9 was significantly decreased at 24, 48, and 72 h after SCI compared with the control group, and the activity of MMP-9 was significantly reduced at 72 h after SCI. In contrast, there were no significant changes in the MMP-2 level in both groups during the experimental period. Melatonin treatment following photochemically induced SCI in rats significantly ameliorated the functional deficits. On histopathologic examination, the lesion size in the spinal cord after photothrombotic insult was significantly reduced by melatonin administration. This study showed that the up-regulation of MMP-9 correlated with the secondary damage after SCI in rats. The results of this study suggest that the ability of melatonin to reduce secondary tissue damage is intimately related to the reduction of MMP-9 expression, resulting in functional improvement.

Vasospasm after Collagenase Clostridium Histolyticum Infiltration in Dupuytren’s Contracture

Treatment with collagenase clostridium histolyticum has been shown to be effective at the short-and mid-term against Dupuytrens contracture in which cords have formed. As with any new drug, pharmacovigilance studies will allow for reporting new complications with the treatment. We present a clinical case of vasospasm after collagenase clostridium histolyticum infiltration in a patient with a 60 ∫affectation of the proximal interph alangeal joint forming an ulnar cord of fifth radius in the left hand. Evolution at one year presents the cord in the same contracture as before, and no vascular alteration. In our opinion, most complications from infiltration with collagenase clostridium histolyticum take place when the treatment is performed and are due to extravasation of the infiltration into healthy tissue. In cases of greater extravasation, vessels may be affected causing transient vasospasms due to the local action of the enzyme, to gether with a secondary inflammatory reaction to the collagenase action.

Early high volume lung lavage for acute severe smoke inhalation injury in dogs

The aim of the present study was to investigate the safety and short‑term results of early high volume lung lavage in the treatment of acute severe smoke inhalation injuries in dogs. A high‑volume normal saline complex solution lavage in the left lung was performed 1 h subsequent to bilateral pulmonary acute severe sawdust smoke inhalation injury in dogs. Lavage of the right lung was conducted following an interval of 30 min or 4 h. The perfluorodecalin lavage was performed in dogs with unilateral pulmonary acute severe sawdust smoke inhalation injury. The present study identified that lavage with an interval of 4 h between two lungs was safer compared with a 30‑min interval. Following lavage, the increase in the levels of free radical metabolites and inflammatory mediators in the lung homogenate was reduced. Acute severe smoke inhalation injury in one lung evidently caused a secondary injury to the other lung in the dogs. Perfluorodecalin lavage did not achieve the same effect in cleansing the lungs as the normal saline, but a greater comprehensive short‑term outcome was obtained. These observations demonstrated that early high‑volume lung lavage following severe smoke inhalation injury could relieve primary injuries and secondary local and general inflammatory reactions in dogs. An improved comprehensive short‑term outcome was obtained in the perfluorodecalin‑lavaged dogs.

Total glucosides of paeony inhibit the proliferation of fibroblast-like synoviocytes through the regulation of G proteins in rats with collagen-induced arthritis

The aim of this study was to investigate the expression of G proteins in fibroblast-like synoviocytes (FLSs) from rats with collagen-induced arthritis (CIA) and to determine the effect of total glucosides of paeony (TGP). CIA rats were induced with chicken type II collagen (CCII) in Freund's complete adjuvant. The rats with experimental arthritis were randomly separated into five groups and then treated with TGP (25, 50, and 100mg/kg) from days 14 to 35 after immunization. The secondary inflammatory reactions were evaluated through the polyarthritis index and histopathological changes. The level of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The FLS proliferation response was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The toxin-catalyzed ADP-ribosylation of G proteins was performed through autoradiography. The results show that TGP (25, 50, and 100mg/kg) significantly decreased the arthritis scores of CIA rats and improved the histopathological changes. TGP inhibited the proliferation of FLSs and increased the level of cAMP. Moreover, the FLS proliferation and the level of Gαi expression were significantly increased, but the level of Gαs expression was decreased after stimulation with IL-1β (10ng/ml) in vitro. TGP (12.5 and 62.5μg/ml) significantly inhibited the FLS proliferation and regulated the balance between Gαi and Gαs. These results demonstrate that TGP may exert its anti-inflammatory effects through the suppression of FLS proliferation, which may be associated with its ability to regulate the balance of G proteins. Thus, TGP may have potential as a therapeutic agent for the treatment of rheumatoid arthritis.

TNFR2 maintains adequate IL-12 production by dendritic cells in inflammatory responses by regulating endogenous TNF levels

Sepsis-induced immune reactions are reduced in TNF receptor 2 (TNFR2)-deficient mice as previously shown. In order to elucidate the underlying mechanisms, the functional integrity of myeloid cells of TNFR2-deficient mice was analyzed and compared to wild type (WT) mice. The capacity of dendritic cells to produce IL-12 was strongly impaired in TNF-deficient mice, mirroring impaired production of IL-12 by WT dendritic cells in sepsis or after LPS or TNF pre-treatment. In addition, TNFR2-deficient mice were refractory to LPS pre-treatment and also to hyper-sensitization by inactivated Propionibacterium acnes, indicating habituation to inflammatory stimuli by the immune response when TNFR2 is lacking. Constitutive expression of TNF mRNA in kidney, liver, spleen, colon and lung tissue, and the presence of soluble TNFR2 in urine of healthy WT mice supported the conclusion that TNF is continuously present in naïve mice and controlled by soluble TNFR2. In TNFR2-deficient mice endogenous TNF levels cannot be balanced and the continuous exposure to enhanced TNF levels impairs dendritic cell function. In conclusion, TNF pre-exposure suppresses secondary inflammatory reactions of myeloid cells; therefore, continuous control of endogenous TNF by soluble TNFR2 seems to be essential for the maintenance of adequate sensitivity to inflammatory stimuli.

Toxicological aspects of injectable gold-hyaluronan combination as a treatment for neuroinflammation.

Secondary inflammatory reactions to stroke or trauma contribute to irreplaceable loss of brain tissue of the affected patients. Likewise, neuroinflammatory processes are the main pathophysiological feature in Multiple Sclerosis (MS), a common neurodegenerative disease among young adults. In the search for safe and efficient ways to reduce inflammation within nervous tissue older immunosuppressive remedies have been re-investigated. The anti-inflammatory properties of gold salts are well known but result in uncontrollable systemic spread of gold ions, generating side effects such as nephrotoxicity, limiting their use. Recent studies have circumvented this obstacle by introducing metallic gold implants as a localized source of immune-modulating gold ions and suspension in hyaluronic acid (HA) enables injection of small amounts of gold in the natural spaces of the brain. By injecting >25 μm gold beads in HA intracerebrally we recently showed a slowing of disease progression in a rodent model of MS. The toxicological aspects were, however, not assessed. The present study investigates the viability of neuronal and macrophage cell cultures exposed to the gold/HA combination and the possible risk associated with unilateral gold/HA injection in young Balb/CA mice in the first 7 to 21 days of gold-exposure. Tracing by autometallography of gold accumulations throughout the brain exhibited sparse gold uptake in glia and neurons of hippocampus and cortex, and striatum and cerebellum were void of staining. No systemic spread of gold was seen in liver or kidney, nor were there signs of obstruction of the ventricular system. Both cell cultures of J774 macrophages and CCL neurons accumulated gold from gold/HA-exposure with no signs of reduced viability. In conclusion, our findings indicate that gold/HA is not overtly neuro- or cytotoxic, nor does intraventricular exposure result in widespread gold accumulation or tissue damage, warranting further studies into the pharmacological properties of this novel form of gold treatment.